Process for the synthesis of enantiomeric indanylamine derivatives

ABSTRACT

A process for manufacturing (R)-propynylaminoindans, and alternatively, a process for manufacturing (S)-propynylaminoindans. The chiral propynylaminoindans include alkoxy or alkylcarbamates derivatives. The process comprises transfer or pressure hydrogenation in the presence of an optically active catalyst to reduce 1-indanones. The chiral product, either (S)- or (R)-indanols undergo nucleophilic substitution to produce the named product. In an additional aspect, the invention relates to novel intermediates and compounds, namely, substituted indanones, substituted (S)-indanols and substituted (R)-indanols.

FIELD OF INVENTION

This invention relates to processes for preparation of indanylaminederivatives.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,532,415 discloses R(+)-N-propargyl-1-aminoindan(R(+)PAI), its preparation, and various pharmaceutically acceptablesalts thereof. R(+)PAI and salts thereof have been shown to be selectiveinhibitors of MAO-B, useful in treating Parkinson's disease and variousother conditions.

Indanylamine and aminotetralin derivative compounds, such as those ofFormula I below, are useful to treat depression, Attention DeficitDisorder (ADD), Attention Deficit and Hyperactivity Disorder (ADHD),Tourett's Syndrome, Alzheimer's Disease and other dementias as describedin PCT application publication WO98/27055. The indanylamine derivativesdisclosed have been shown to have biological effects in animal models ofneurological disease.

Formula I is:

wherein b is 1 or 2; m is from 0-3, Y is O or S, X is halo, R₄ ishydrogen or C₁₋₄ alkyl, R₅ is hydrogen, C₁₋₄ alkyl, or optionallysubstituted propargyl and R₆ and R₇ are each independently hydrogen,C₁₋₈ alkyl, C₆₋₁₂ aryl, C₆₋₁₂ aralkyl, each optionally halo substituted.

One compound disclosed in the PCT application publication is(R)-6-(N-methyl, N-ethyl-carbamoyloxy)-N′-propargyl-1-aminoindan, alsoknown as (3R)-3-(prop-2-ynylamino)-2,3,-dihydro-1H-inden-5-ylethylmethylcarbamate. Salts thereof are also disclosed, including a ½L-tartrate salt. This salt has been given the nonproprietary nameladostigil tartrate. Its CAS registry number is 209394-46-7.

PCT application publication WO98/27055 also discloses methods for thepreparation of indanylamine and aminotetralin derivatives of Formula Iusing, for example, as starting materials 3-amino-indan-5-ol or6-methoxy-indan-1-ylamine. Methods of preparation of the startingmaterials are also disclosed. 6-Methoxy-indan-1-ylamine is prepared byconversion of 6-methoxy-indan-1-one to 6-methoxy-indan-1-one oximefollowed by reduction to 6-methoxy-indan-1-ylamine. Alternatively6-methoxy-1-aminoindan can be prepared by reductive amination (NaCNBH₃and NH₄OAc) of 6-methoxy-indan-1-one to 6-methoxy-indan-1-ylamine.3-Amino-indan-5-ol can be prepared by using a Friedel-Crafts acylationof an N-protected 3-aminoindan, followed by a Baeyer-Villiger oxidationwith subsequent hydrolysis.

These methods for producing starting materials such as3-amino-indan-5-ol and 6-methoxy-indan-1-ylamine are accompanied by lowyields. Thus, there is a need for reliable processes to produceindanylamine and aminotetralin derivatives in high yields asintermediates to prepare aminoindan derivatives and specificallycompounds of Formula I, wherein the processes are suitable forindustrial production.

Additionally, there is a need for efficient ways of producingenantiomerically enriched indanylamine derivatives. The prior art doesnot disclose sufficiently efficient methods of enantiomericpurification. In the prior art method of optical resolution of eitherthe starting material or of the end product via diastereomeric saltformation, the undesired enantiomer is “wasted,” and the yield isthereby decreased. Another method disclosed in the prior art, resolutionusing a chiral chromatographic column, is not feasible for a large scalesynthesis.

Small scale asymmetric reduction of 1-indanone by transfer hydrogenationusing silica-immobilized Ru-TsDPEN catalysts is described by Liu et al.Org. Lett., Vol. 6, 2004, Efficient Heterogeneous Asymmetric TransferHydrogenation of Ketones Using Highly Recyclable and AccessibleSilica-immobilized Ru-TsDPEN Catalysts.

SUMMARY OF THE INVENTION

The present invention relates to a process for manufacturing a compoundof the formula:

wherein R₁ is H, —OR₂, or

wherein R₂ is C₁-C₄ alkyl, and R₃ is H or C₁-C₄ alkyl.

In an embodiment, the first step of the process of the present invention1-indanones are reduced by transfer or pressure hydrogenation in thepresence of an optically active catalyst and a hydrogen donor topreferentially produce an (S)-indanol. The optically active catalystcomprises a transition metal, such as Ru, and one or more opticallyactive ligands. In the next step, activation of an (S)-indanol at thecarbon in the —OH substituted benzylic position, by converting the —OHto a leaving group for subsequent reaction with a nucleophile, such aspropargylamine, results in aminoindan derivatives of Formula V.

The present invention additionally relates to a process formanufacturing a compound of the formula:

wherein R₁, R₂, and R₃ are as defined above.

In an additional embodiment, the first step of the process of thepresent invention 1-indanones are reduced by transfer or pressurehydrogenation in the presence of an optically active catalyst and ahydrogen donor to preferentially produce an (R)-indanol. The opticallyactive catalyst comprises a transition metal, such as Ru, and one ormore optically active ligands. In the next step, activation of an(R)-indanol at the carbon in the —OH substituted benzylic position, byconverting the —OH to a leaving group for subsequent reaction with anucleophile, such as propargylamine, results in (S)-aminoindanderivatives of Formula VII.

In a another aspect, the invention relates to novel intermediates,namely, substituted indanones, and substituted (S)-indanols andsubstituted (R)-indanols. Both the improved process and novelintermediates are useful in the preparation of therapeutically activecompounds used for the treatment of disorders of the central nervoussystem such as those described above.

DESCRIPTION OF THE FIGURES

FIGS. 1 and 2 illustrate structural formulas of various ligands andcatalysts for use in the instant invention.

DETAILED DESCRIPTION OF THE INVENTION

The processes of the present invention produce chiral indanylaminederivatives from readily available, pro-chiral starting materials. Theprocesses of the present invention require few steps and areindustrially applicable on a large scale. One advantage of the processesof the present invention is no need to “waste” starting material bydiastereomeric salt formation. In addition, the processes do not requirelarge amount of solvents as required in chromatographic separations. Thecompounds produced by the processes of the current invention aresuitable for use as pharmaceuticals, or starting materials orintermediates in the production of a variety of pharmaceuticals, forexample those presented in Formula I above.

In various embodiments, halo includes fluoro, chloro, bromo, or iodo.Halides comprise halo groups, such as fluoro, chloro, bromo, or iodo.Alkyl, alkoxy, etc., include both straight and branched groups; butreference to an individual radical such as “propyl” embraces only thestraight chain radical, a branched chain isomer such as “isopropyl”being specifically referred to.

“Alkyl” includes linear alkyls, branched alkyls, and cycloalkyls.Additionally, the alkyls may be substituted with alkoxy, halo, and likesubstitutents. In some embodiments, alkyl is a C₁₋₁₀alkyl, in otherembodiments, alkyl is a C₁₋₄alkyl. Example alkyl groups include:C₁₋₄alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, iso-butyl,sec-butyl, tert-butyl; C₁₋₁₀alkyl, such as methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, 3-pentyl,hexyl, heptyl, octyl, nonyl and decyl; (C₃₋₁₂)cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, bicyclic, or multi-cyclic substituents, such as of theformulas

“Alkoxy” includes —O-alkyl in which the alkyl is as described above.Example alkoxys include, but are not limited to: methoxy, ethoxy,n-propoxy, n-butoxy, n-pentoxy, hexyloxy, and heptyloxy.

“Acyl” includes —C(═O)R, for example, —C(═O)H, —C(═O)alkyl, - andC(═O)halo, in which the alkyl is as described above. Specific examplesof —C(═O)alkyl include, but are not limited to: acetyl, propanoyl,butanoyl, pentanoyl, 4-methylpentanoyl, hexanoyl, or heptanoyl.

“Aryl” includes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to twenty ring atoms in which at least onering is aromatic. Aryl (Ar) can include substituted aryls, such as aphenyl radical having from 1 to 5 substituents, for example, alkyl,alkoxy, halo, and like substituents. In some embodiments, aryl is aC₆₋₁₈ aryl which is either unsubstituted or substituted. Example arylsinclude, but are not limited to: phenyl, naphthyl, anthracenyl,phenanthrenyl, fluorenyl, tetrahydronaphthyl, or indanyl.

“Alkylaryl” includes an alkyl-aryl wherein the alkyl and the aryl are asdescribed above. Example alkylaryls include, but are not limited to:benzyl, 2-phenethyl and naphthylenemethyl.

The carbon atom content of various hydrocarbon-containing moieties isindicated by a prefix designating a lower and upper number of carbonatoms in the moiety, i.e., the prefix C_(i-j) indicates a moiety of theinteger “i” to the integer “j” carbon atoms, inclusive. Thus, forexample, (C₁-C₁₀)alkyl or C₁₋₁₀alkyl refers to alkyl of one to tencarbon atoms, inclusive, and (C₁-C₄)alkyl or C₁₋₄alkyl refers to alkylof one to four carbon atoms, inclusive.

The compounds of the present disclosure are generally named according tothe IUPAC nomenclature system. Abbreviations, which are well known toone of ordinary skill in the art, may be used (e.g., “Ph” for phenyl,“Me” for methyl, “Et” for ethyl, “h” for hour or hours, “g” or “gm” forgram(s), “mL” for milliliters, and “rt” for room temperature).

“About” modifying, for example, the quantity of an ingredient in acomposition, concentrations, volumes, process temperature, process time,yields, flow rates, pressures, and like values, and ranges thereof,employed in describing the embodiments of the disclosure, refers tovariation in the numerical quantity that can occur, for example, throughtypical measuring and handling procedures used for making compounds,compositions, concentrates or use formulations; through inadvertenterror in these procedures; through differences in the manufacture,source, or purity of starting materials or ingredients used to carry outthe methods; and like proximate considerations. The term “about” alsoencompasses amounts that differ due to aging of a formulation with aparticular initial concentration or mixture, and amounts that differ dueto mixing or processing a formulation with a particular initialconcentration or mixture. Whether modified by the term “about” theclaims appended hereto include equivalents to these quantities.

The indefinite article “a” or “an” and its corresponding definitearticle “the” as used herein means at least one, or one or more, unlessspecified otherwise.

The enantiopurity of a product can be expressed in the form of %enantiomeric excess (% e.e.) which is calculated as follows, wherein“maj” is the relative quantity of the major enantiomer and “min” is therelative quantity of the minor enantiomer.

${\%\mspace{14mu}{e.e.}} = {\frac{{maj} - \min}{{maj} + \min} \times 100}$

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents. The compounds of the disclosure include compounds offormulas (II through V) and like compounds having any combination of thevalues, specific values, more specific values, and preferred valuesdescribed herein.

One process of the present invention is represented schematically below.The process of the invention can be divided into multiple steps: (1)hydrogenation of a 1-indanone or derivative thereof in the presence ofan optically active catalyst into the corresponding (S)-indanol; and (2)derivatization of the hydroxyl moiety of the indanol into a suitableleaving group (3) thereby facilitating an SN2 substitution at thebenzylic carbon by propylgarylamine.

In additional embodiments, the method of the present invention produces(R)-indanol intermediates (VI) and (S)-indanylamine derivatives,including derivatives illustrated by formula VII below.

In formulas II through VII, R₁ is H, —OR₂, or

wherein R₂ is C₁-C₄ alkyl, and R₃ is H or C₁-C₄ alkyl, and R₄ is asulphonate ester or halide. In an embodiment, R₁ is H. In an anotherembodiment, R₁ is —O(C═O)NR₂R₃, wherein R₂ is methyl and R₃ is ethyl. Ina further embodiment, R₂ and R₃ are methyl.

The first step of the improved process relates to reduction of anindanone in the presence of an optically active catalyst and a hydrogendonor in an appropriate solvent. In some embodiments, the indanone is acompound of Formula II, wherein R₁, R₂ and R₃ are as defined above.

In an embodiment, the indanone is reduced by transfer hydrogenation.Transfer hydrogenation within the context of the present invention, is aprocess in which a double bond, for instance, a double bond betweencarbon and oxygen, is hydrogenated in the presence of an organicmolecule, a hydrogen donor, other than hydrogen gas, and in the presenceof a catalyst. The reactants are combined in a suitable solvent, such asan organic aprotic solvent. An optically active catalyst is used toattain enantiomeric selectivity in the transfer hydrogenation reaction.The nature of the enantiomeric selectivity is affected by the opticallyactive catalyst used. See Table 1. In an embodiment, the hydrogenationis carried out in the presence of an azeotrope comprising a hydrogendonor and an organic base, such as triethylamine. In an embodiment, thetransfer hydrogenation is carried out in the presence of a formicacid-triethylamine azeotrope.

A hydrogen donor is a molecule which acts to reduce a double bond bydonating hydrogen atoms to the reduced molecule. Hydrogen donorssuitable for use the process of transfer hydrogenation include organicacids and salts thereof. Hydrogen donors which are suitable for use intransfer hydrogenation include, but are not limited to: formic acid,ammonium formate, isopropanol, cyclohexene, and 1,3-cyclohexadiene.

Within the context of the invention, an organic aprotic solvent is anorganic solvent which does not act as a proton donor or acceptor.Examples of aprotic organic solvents include, but are not limited to,acetonitrile, dichloromethane, toluene, and alkyl ethers. In anembodiment, the organic aprotic solvent is dichloromethane.

In an alternative embodiment, the indanone is reduced by pressurehydrogenation. Pressure hydrogenation is a process in which a doublebond, for instance, a double bond between carbon and oxygen, ishydrogenated in the presence of hydrogen gas as a hydrogen donor, and inthe presence of a catalyst. An optically active catalyst is used toattain enantiomeric selectivity in the pressure hydrogenation reaction.

The reaction is performed under hydrogen gas at a pressure of between0.1 to 15 bars (10 to 1500 kPa), under a temperature range of between 10to 80° C., for a period of time in the range of 1 to 24 hours. In anembodiment, is performed under hydrogen gas at a pressure at about 8 to12 bars (800 to 1200 kPa). In some embodiments, the reaction temperatureis maintained within a range of between about 30-40° C. In oneembodiment, the reaction is performed under hydrogen gas pressure ofabout 10 bars (1000 kPa), at a temperature of about 40° C., and forabout 18 hours.

An advantage of catalytic transfer hydrogenation and catalytic pressurehydrogenation is the requirement for small amounts of catalysts. Theeffective amount of catalyst may be an amount from 1:100 to 1:1000 ratioof catalyst (mol) to starting indanone (mol). In one embodiment, theamount of optically active catalyst is about 1:100 to about 1:250mol/mol in relation to the indanone starting material.

Within the context of the present invention, an optically activecatalyst is used with either transfer hydrogenation or pressurehydrogenation. An optically active catalyst is a catalyst whichtransforms an achiral center, for instance, a double bond between carbonand oxygen to a chiral center, and in proper reaction conditions, theoutcome is a single enantiomer, or a mixture of enantiomers in which oneof the enantiomers is in excess. Structures and names of some suitableoptically active ligands and catalysts can be seen in FIGS. 1 and 2.Optically active catalysts generally include transition metals complexedto one or more chiral ligands. Examples of suitable transition metalsinclude Ru, Rh, and Ir. In an embodiment, the optically active catalystcomprises Ru.

Within the context of this invention, the term “catalyst” can also referto a pre-catalyst. A pre-catalyst is a molecule, or complex, in a stableform which is not an active catalyst before being added to the reactionmixture, but becomes an active catalyst under specific conditions withinthe reaction mixture.

Examples of optically active catalysts or precatalysts suitable for usein the methods of the present invention include, but are not limited to[(R)-HexaPHEMP RuCl₂ (R,R)-DACH], [(R)-HexaPHEMP RuCl₂ (R,R)-DPEN],[(R)-PhanePhos RuCl₂ (S,S)-DACH], [(S)-PhanePhos RuCl₂ (R,R)-DPEN],[(S)-MeO-Xylyl-PhanePhos RuCl₂ (R,R)-DPEN], [(R)-MeO-Xylyl-PhanePhosRuCl₂ (S,S)-DACH], [(S)-SynPhos RuCl₂ (S,S)-DPEN], [(S)-Xylyl-BINAPRuCl₂ (S,S)-DPEN], [(S)-F-Phenyl-PhanePhos RuCl₂ (R,R)-DPEN],[(S)-MeO-Phenyl-PhanePhos RuCl₂ (R,R)-DPEN], [(s)-MeO-Phenyl-PhanePhosRuCl₂ (R,R)-DACH], [(R,R)-Me-DuPhos RuCl₂ (R,R)-DPEN], [(R)-BINAP RuCl₂(R)-DAIPEN], [(R,R)-Et-DuPhos RuCl₂ (R,R)-DACH], [R,R-TsDPEN (Ru)(p-cymene) Cl], and [S,S-TsDPEN (Ru) (p-cymene) Cl]. In an embodiment,the method of the present invention comprises S,S-TsDPEN (Ru) (p-cymene)Cl as an optically active catalyst.

In a second step, either (S)- or (R)-indanol is activated at the —OHsubstituted benzylic carbon for nucleophilic substitution. In anembodiment, the hydroxyl moiety is derivatized to form a suitableleaving group for nucleophilic substitution. In an embodiment, thenucleophilic substitution is SN2. The second step is based on methods ofnucleophilic substitution described in the literature, in an appropriatesolvent. (See March's Advanced Organic Chemistry; Michael B. Smith andJerry March, 5^(th) edition, Chapter 10.) In an embodiment, thenucleophile is propargylamine.

Within the context of the invention, a leaving group is an atom (or agroup of atoms) with electron withdrawing ability that is displaced as astable species, taking with it the bonding electrons. In an embodiment,the leaving group will facilitate an SN2 reaction between thesubstituted benzylic carbon and the propargylamine. Examples of suitableleaving groups include sulfonate esters and halides. In an embodiment,the leaving group is methane sulfonate ester.

The process of the present invention may further comprise the conversionof a product into a pharmaceutically acceptable salt. In the practice ofthis invention, pharmaceutically acceptable salts include, but are notlimited to, the mesylate, maleate, fumarate, tartrate, hydrochloride,hydrobromide, esylate, p-toluenesulfonate, benzoate, acetate, phosphateand sulfate salts. The present invention additionally comprises productsas pharmaceutically acceptable salts.

EXAMPLES

Suitable indanone starting materials and other materials described arecommercially available. Derivatization of indanone starting materials,such as 6-hydroxy-1-indanone, to form substituted starting materials foruse in the processes of the present invention is described below.

Example 1 Dimethyl-carbamic acid 3-oxo-indan-5-yl ester

Dimethyl carbamyl chloride (7.7 mL, 83.3 mmol) was added dropwise to astirred suspension of 6-hydroxy-1-indanone (10.290 g, 69.4 mmol) andpotassium carbonate (12.48 g, 90.3 mmol) in DMF (50 mL) at 0° C.(external) over a period of 30 minutes. One hour after the addition wascomplete the cold bath was removed and the reaction was allowed to warmslowly to room temperature over 2 hours. The reaction mixture wasdiluted with methyl tert-butyl ether (50 mL) and water (100 mL) and theresultant solid was collected by filtration and washed with water (50mL) and then methyl tert-butyl ether (50 mL). The collected material wasdried under vacuum overnight. The crude product was purified by solventslurry in methyl tert-butyl ether (50 mL) before being collected byfiltration, washed with additional methyl tert-butyl ether (20 mL) anddried to afford the title compound (16) (14.877 g, 98%). 1H NMR (400MHz, CDCl3) δ ppm 7.47-7.45 (2H, m, Ar), 7.36 (1H, dd, J 8 and 2, Ar),3.14-3.11 [5H, m, OCCH2 and Me, incl. at 3.11 (3H, s, Me)], 3.02 (3H, s,Me) and 2.74-2.71 (2H, m, OCCH2CH2).

Example 2 Dimethyl-carbamic acid 3-hydroxy-indan-5-yl ester

Example 2a Transfer Hydrogenation

Formic acid (4.3 mL, 114.0 mmol) was added dropwise to a stirredsolution of dimethyl-carbamic acid 3-oxo-indan-5-yl ester (5.00 g, 22.8mmol), (R,R)-TsDPEN Ru (p-cymene)Cl (58 mg, 0.1 mmol) and triethylamine(15.9 mL, 114.0 mmol) in dichloromethane (21 mL) at 35° C. (external)over a period of 50 minutes. After 20 hours, additional (R,R)-TsDPEN Ru(p-cymene)Cl (58 mg, 0.1 mmol) formic acid (0.9 mL, 22.8 mmol) andtriethylamine (3.2 mL, 22.8 mmol) were added to the reaction and heatingwas continued for 19 hours. The reaction was allowed to cool beforebeing poured into saturated aqueous sodium hydrogen carbonate solution(150 mL) and was extracted with dichloromethane (150 mL+100 mL). Theorganic material was dried (MgSO₄), filtered and concentrated underreduced pressure to afford the R-enantiomer of the title compound (5.144g, quant.). Analysis of this material by chiral LC indicated it to be98% e.e.

Example 2b Pressure Hydrogenation

[(R,R)-Me-DuPhos RuCl₂ (R,R)-DPEN] (1.7 mg, 0.002 mmol) anddimethyl-carbamic acid 3-oxo-indan-5-yl ester (110 mg, 0.5 mmol) wereplaced in a glass liner within an Argonaut Endeavor pressure vessel. Thevessel was assembled. The vessel was pressurised to 10 bar with nitrogenand the pressure was released. This was repeated a further two times. Asolution of potassium tert-butoxide [3 ml (of a solution of commercial0.25 ml of 1.0 M potassium tert-butoxide solution in tert-butanol madeup to 30 ml with dry degassed 2-propanol), 0.025 mmol)] was added to thevessel. The vessel was pressurised to 10 bar with nitrogen and thepressure was released. This was repeated one more time. The vessel washeated to 40° C. (internal) with stirring before being pressurised to 10bar with hydrogen. After 18 hours, the vessel was allowed to cool toroom temperature before being vented and the reaction solutionconcentrated under reduced pressure to afford the R-enantiomer of titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.20 (1H, d, J 9, Ar), 7.14 (1H,d, J 3, Ar), 6.98 (1H, dd, J 8 and 2, Ar), 5.20 (1H, dd, J 6 and 6,CHOH), 3.10 (3H, s, Me), 3.04-2.97 [4H, m, OCHCH₂CHH and Me, incl. at3.01 (3H, s, Me)], 2.83-2.72 (1H, m, OCHCH₂CHH), 2.59-2.49 (1H, m,OCHCHH), 1.99-1.91 (1H, m, OCHCHH) and 1.84 (1H, brs, OH). Analysis ofthis material by chiral LC indicated it to be 73% e.e.

Similar procedures were performed using pre-catalysts as listed below inTable 1. The conversion percent enantiomeric excess percent are listedin the table for each example.

TABLE 1 1 [(S)-Xylyl-HexaPHEMP RuCl₂ (S,S)-DPEN] >95 30 (S) 2[(R)-HexaPHEMP RuCl₂ (R,R)-DACH] >95 26 (R) 3 [(R)-HexaPHEMP RuCl₂(R,R)-DPEN] >95 35 (R) 4 [(R)-PhanePhos RuCl₂ (S,S)-DACH] >95 16 (S) 5[(S)-PhanePhos RuCl₂ (R,R)-DPEN] >95 37 (R) 6 [(S)-MeO-Xylyl-PhanePhosRuCl₂ (R,R)-DPEN] >95 rac 7 [(R)-MeO-Xylyl-PhanePhos RuCl₂(S,S)-DACH] >95 62 (S) 8 [(S)-Tol-BINAP RuCl₂ (S,S)-DPEN] >95 28 (S) 9[(S)-SynPhos RuCl₂ (S,S)-DPEN] >95 35 (S) 10 [(S)-Xylyl-BINAP RuCl₂(S,S)-DPEN] >95 38 (S) 11 [(S)-F-Phenyl-PhanePhos RuCl₂ (R,R)-DPEN] >9549 (R) 12 [(S)-MeO-Phenyl-PhanePhos RuCl₂ (R,R)-DPEN] >95 35 (R) 13[(S)-MeO-Phenyl-PhanePhos RuCl₂ (R,R)-DACH] >95 23 (R) 14[(S)-Xylyl-PhanePhos RuCl₂ (R,R)-DPEN] >95 62 (R) 15 [(R,R)-Me-DuPhosRuCl₂ (R,R)-DPEN] >95 73 (R) 16 [(R)-BINAP RuCl₂ (R)-DAIPEN] >95 30 (R)17 [(R,R)-Et-DuPhos RuCl₂ (R,R)-DACH] >95 27 (R) † Conversion estimatedfrom the ¹H NMR of the crude material. ‡ Enantiomeric excess wasdetermined by chiral LC analysis. Configuration was assigned bycomparison with the ethylmethyl analog.

Comparative Example 2c Racemic Form

Sodium borohydride (66 mg, 1.7 mmol) was added to a stirred suspensionof dimethyl-carbamic acid 3-oxo-indan-5-yl ester (381 mg, 1.7 mmol) in amixture for THF (5 mL) and water (0.5 mL) at 0° C. (external). Afterstirring at this temperature for 2 hour, saturated aqueous ammoniumchloride solution (10 mL) and ethyl acetate (20 mL) was added. Theorganic layer was dried (MgSO₄), filtered and concentrated under reducedpressure to afford a racemic mixture of the title compound (343 mg,89%.). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.20 (1H, d, J 9, Ar), 7.14 (1H, d,J 3, Ar), 6.98 (1H, dd, J 8 and 2, Ar), 5.20 (1H, dd, J 6 and 6, CHOH),3.10 (3H, s, Me), 3.04-2.97 [4H, m, OCHCH₂CHH and Me, incl. at 3.01 (3H,s, Me)], 2.83-2.72 (1H, m, OCHCH₂CHH), 2.59-2.49 (1H, m, OCHCHH),1.99-1.91 (1H, m, OCHCHH) and 1.84 (1H, brs, OH).

Example 3 Ethylmethyl-carbamic acid 3-oxo-indan-5-yl ester

Ethylmethyl carbamyl chloride (15.5 g, 127.57 mmol) was added to astirred suspension of 6-hydroxy-1-indanone (17.2 g, 116.1 mmol) andpotassium carbonate (31.8 g, 188 mmol) in acetonitrile (800 mL) at roomtemperature over a period of 15 minutes. The reaction mixture was heatedto reflux and refluxed for 18 hours. The reaction mixture was cooled toambient temperature, the solvent evaporated and the residue was dilutedwith water (250 mL) and extracted three times with toluene (250 mL). Thecombined organic phase was dried on MgSO₄ and toluene was evaporated ina rotary evaporator. The crude crystalline product was purified bycrystallization from 2-propanol (200 mL), collected by filtration, anddried under vacuum at 50° C. to afford the title compound (22 g, 81.5%).¹H NMR (300 MHz, CDCl₃) δ ppm 7.47-7.44 (2H, m, Ar), 7.36 (1H, dd, J 8.4and 2.1, Ar), 3.52-3.37 (2H, m, NCH₂CH₃), 3.14-3.108 [2H, m, OCCH₂CH₂and incl. NCH₃ (two rotamers), at 3.08 and 2.99 (3H, s, Me)], 2.74-2.71(2H, m, OCCH₂CH₂) and 1.25 and 1.19 (two rotamers) (3H,two triplets, J6.9). Mass Spectrum (FAB+) [MH⁺]=234

Example 4 Ethyl-methyl-carbamic acid 3-hydroxy-indan-5yl ester

Example 4a Transfer Hydrogenation

Formic acid (6.7 mL, 178.6 mmol) was added dropwise to a stirredsolution of ethyl-methyl-carbamic acid 3-oxo-indan-5-yl ester (8.33 g,35.7 mmol), (R,R)-TsDPEN Ru (p-cymene)Cl (114 mg, 0.2 mmol) andtriethylamine (24.9 mL, 178.6 mmol) in dichloromethane (31 mL) at 35° C.(external) over a period of 30 minutes. After 18 hours, additional(R,R)-TsDPEN Ru (p-cymene) Cl (114 mg, 0.2 mmol) formic acid (1.3 mL,35.7 mmol) and triethylamine (5.0 mL, 35.7 mmol) were added to thereaction and heating was continued for 24 hours. The reaction wasallowed to cool before being poured into saturated aqueous sodiumhydrogen carbonate solution (200 mL) and was extracted withdichloromethane (200 mL+150 mL). The organic material was washed withbrine (100 mL), dried (MgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by passage through a pad ofsilica using methyl tert-butyl ether as eluant to afford theR-enantiomer of the title compound (8.462 g, quant.). Analysis of thismaterial by chiral LC indicated it to be 99% e.e.

Example 4b Transfer Hydrogenation

The procedure described in example 4a is repeated with (S,S)-TsDPEN Ru(p-cymene)Cl in place of (R,R)-TsDPEN Ru (p-cymene)Cl. The S-enantiomerof the title compound is attained.

Comparative Example 4c Racemic Form

Sodium borohydride (50 mg, 1.3 mmol) was added to a stirred suspensionof ethyl-methyl-carbamic acid 3-oxo-indan-5-yl ester (306 mg, 1.3 mmol)in methanol (5 mL) at room temperature. After stirring at thistemperature for 2 hour, saturated aqueous ammonium chloride solution (10mL), water (10 mL) and ethyl acetate (20 mL) were added. The layers wereseparated and then the aqueous was extracted with additional ethylacetate (20 mL). The combined organic layers were dried (MgSO₄),filtered and concentrated under reduced pressure to afford a racemicmixture of the title compound (330 mg, quant.). ¹H NMR (400 MHz, CDCl₃)δ ppm 7.20 (1H, d, J 8, Ar), 7.14 (1H, s, Ar), 6.98 (1H, d, J 8, Ar),5.20 (1H, dd, J 6 and 6, CHOH), 3.47 (rotamer A, 1H, q, J 7, MeCH₂N),3.40 (rotamer B, 1H, q, J 8, MeCH₂N), 3.06-2.97 [4H, MeN and OCHCH₂CHH,incl. at 3.06 (rotamer A, 1.5H, s, MeN) and 2.99 (rotamer B, 1.5H, s,MeN)], 2.81-2.74 (1H, m, OCHCH₂CHH), 2.55-2.47 (1H, m, OCHCHH),1.99-1.91 (1H, m, OCHCHH), 1.66 (1H, brs, OH), 1.24 (rotamer A, 1.5H, t,J 7, MeCH₂N) and 1.19 (rotamer B, 1.5H, t, J 7, MeCH₂N).

Example 5 1-Indanol

Formic acid (7.2 mL, 190.7 mmol) was added dropwise to a stirredsolution of 1-indanone (5.09 g, 38.5 mmol), (S,S)-TsDPEN Ru (p-cymene)Cl (231 mg, 0.36 mmol) and triethylamine (26 mL, 186.5 mmol) indichloromethane (50 mL) at 30° C. (internal) under a nitrogen atmosphereover a period of 30 minutes. The internal temperature reached 35° C.during the addition. After stirring for 19 hours at 30° C., ¹H NMRanalysis indicated a conversion of 80%. Additional (S,S)-TsDPEN Ru(p-cymene)Cl (47 mg, 0.07 mmol) was added to the reaction mixturefollowed by formic acid (3 mL, 79.5 mmol) dropwise over 30 minutes.After stirring for 21 hours at 35° C. (internal), ¹H NMR analysisindicated complete conversion. The reaction was allowed to cool to roomtemperature before saturated aqueous sodium hydrogen carbonate solution(100 mL) was added. The two layers were separated then the aqueous layerwas further extracted with dichloromethane (80 mL). The combined organiclayers were washed with water (80 mL), dried (MgSO₄), filtered andconcentrated under reduced pressure. The crude material was purified bypassage trough a pad of silica using methyl tert-butyl ether as eluantto afford the S-enantiomer of the title compound as a red solid. (5.06g, 98%). ¹H NMR (400 MHz, d₆-DMSO) δ ppm 7.37-7.34 (1H, m, Ar),7.26-7.19 (3H, m, Ar), 5.23 (1H, d, J 6, OH), 5.06 (1H, dt, J 6 and 6,CH), 2.97-2.90 (1H, m, CHH), 2.77-2.69 (1H, m, CHH), 2.39-2.31 (1H, m,CHH) and 1.84-1.75 (1H, m, CHH). Analysis of this material by chiral GCindicated it to be 98% e.e.

Example 6 (S)-Dimethyl-carbamic acid 3-prop-2-ynylamino-indan-5-yl ester

Methanesulfonyl anhydride (296 mg, 1.7 mmol) as a solution indichloromethane (1.5 mL+0.5 mL) was added to a stirred solution of(R)-dimethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester (188 mg,0.8 mmol, product of example 1a) and triethylamine (0.47 mL, 3.4 mmol)in dichloromethane (2 mL) at −78° C. (external) over 10 minutes. Thereaction was maintained at this temperature for 1 hour beforepropargylamine (1.20 mL, 17.0 mmol) was added. The reaction was allowedto warm slowly to room temperature overnight before being partitionedbetween ethyl acetate (20 mL) and ice-water (20 mL). The organicmaterial was concentrated under reduced pressure to afford a brown oilwhich was partitioned between methyl tert-butyl ether (10 mL) andaqueous hydrochloric acid (1M, 10 mL). The aqueous layer was basified byaddition of aqueous sodium hydroxide solution (2M, 16 mL) before beingextracted with ethyl acetate (10 mL). This final organic extract wasdried (MgSO₄), filtered and concentrated under reduced pressure toafford the title compound (175 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ ppm7.19 (1H, d, J 8, Ar), 7.09 (1H, d, J 2, Ar), 6.94 (1H, dd, J 8 and 2,Ar), 4.39 (1H, dd, J 6 and 6, CHNH), 3.54 (1H, Dd, J 17 and 3, NCHH),3.49 (1H, Dd, J 16 and 3, HNCHH), 3.09 (3H, s, Me), 3.03-2.96 [4H, m,NCHCHH and Me incl. at 3.00 (3H, s, Me)], 2.83-2.75 (1H, m, NCHCHH),2.48-2.39 (1H, m, NCHCH₂CHH), 2.25 (1H, t, J 2, ≡CH) and 1.92-1.83 (1H,m, NCHCH₂CHH). Analysis of this material by chiral LC indicated it to be70% e.e.

Example 7a (S)-Ethyl-methyl-carbamic acid 3-prop-2-ynylamino-indan-5-ylester

Methanesulfonyl anhydride (1.544 g, 8.9 mmol) as a solution indichloromethane (7.5 mL+2.5 mL) was added to a stirred solution of(R)-ethyl-methyl-carbamic acid 3-hydroxy-indan-5-yl ester (1.04 g, 4.4mmol) and triethylamine (2.5 mL, 17.7 mmol) in dichloromethane (10 mL)at −35° C. (external) over 10 minutes. The reaction was maintained atthis temperature for 45 minutes before propargylamine (3.0 mL, 44.3mmol) was added. The reaction was allowed to warm slowly to roomtemperature overnight before being partitioned between ethyl acetate(100 mL) and ice-water (100 mL). The organic material was concentratedunder reduced pressure to afford a brown oil which was partitionedbetween methyl tert-butyl ether (50 mL) and aqueous hydrochloric acid(1M, 50 mL). The aqueous layer was basified by addition of aqueoussodium hydroxide solution (2M, 40 mL) before being extracted with ethylacetate (50 mL). This final organic extract was dried (MgSO₄), filteredand concentrated under reduced pressure to afford the title compound(842 mg, 70%). ¹H NMR (400 MHz, CDCl₃) δ ppm 7.19 (1H, d, J 8, Ar), 7.09(1H, s, Ar), 6.94 (1H, brd, J, 8, Ar), 4.39 (1H, dd, J 6 and 6, NHCH),3.55 (1H, Dd, J 17 and 2, NCHH), 3.49 (1H, Dd, J 17 and 2, NCHH), 3.46(rotamer A, 1H, q, J 8, MeCHHN), 3.40 (rotamer B, 1H, q, J 7, MeCHHN),3.06 (rotamer A, 1.5H, s, MeN), 3.03-2.95 [2.5H, m, NCHCH₂CHH androtamer B, Me, incl. at 2.98 (rotamer B, 1.5H, s, MeN)], 2.83-2.75 (1H,m, NCHCH₂CHH), 2.48-2.39 (1H, m, NCHCHH), 2.25 (1H, t, J 2, ≡CH),1.92-1.83 (1H, m, NCHCHH), 1.23 (rotamer A, 1.5H, t, J 7, MeN) and 1.18(rotamer B, 1.5H, t, J 7, MeN). Analysis of this material by chiral LCindicated it to be 62% e.e.

Example 7b (R)-Ethyl-methyl-carbamic acid 3-prop-2-ynylamino-indan-5-ylester (ladostigil)

The procedure of example 7a is repeated with (S)-ethyl-methyl-carbamicacid 3-hydroxy-indan-5-yl ester instead of (R)-ethyl-methyl-carbamicacid 3-hydroxy-indan-5-yl ester. The R-enantiomer is produced.

Example 8 N-propargyl-1-(R)aminoindan (Rasagiline)

Methanesulfonyl anhydride (3.0 g, 17.2 mmol) as a solution indichloromethane (8 mL+4 mL) was added to a stirred solution of(S)-1-indanol (1.02 g, 7.6 mmol) and triethylamine (4.4 mL, 31.5 mmol)in dichloromethane (20 mL) at −26° C. (internal, −35° C. external) over10 minutes. During the addition the internal temperature rose to −20° C.The reaction was maintained at −29° C. (internal, −35° C., external) for45 minutes before propargylamine (5 mL, 78 mmol) was added over 2minutes. The reaction was allowed to warm slowly to room temperatureovernight before being portioned between ethyl acetate (50 mL) andice-water (75 mL, pH of solution 9.7). The organic layer wasconcentrated under reduced pressure to afford a brown oil which waspartitioned between methyl tert-butyl ether (50 mL) and aqueoushydrochloric acid (1M, 40 mL, pH of solution <1). The aqueous layer wasbasified to pH>12.5 by addition of aqueous sodium hydroxide solution(2M, 30 mL) before being extracted with ethyl acetate (50 mL+30 mL). Thecombined final organic extracts were dried (MgSO₄), filtered andconcentrated under reduced pressure to afford the title compound as abrown liquid (0.81 g, 68%). Analysis of this material by chiral GCindicated it to be 46% e.e.

Throughout this application various publications, published patentapplications, and published patents are referenced. The disclosures ofthese publications in their entireties are hereby incorporated byreference into this application in order to more fully describe thestate of the art to which this invention pertains.

1. A process for manufacturing a compound of the formula:

wherein R₁ is H, —OR₂, or

wherein R₂ is C₁-C₄ alkyl, and R₃ is H or C₁-C₄ alkyl, the processcomprising: a. reducing an indanone derivative of the formula:

wherein R₁ is defined as above, in the presence of an optically activecatalyst and a hydrogen donor to form a compound of the formula:

b. activating the carbon in the —OH substituted benzylic position of theproduct of step a by converting the —OH to a leaving group; and c.reacting the product of step b with

to form the above desired product.
 2. The process of claim 1 wherein thereducing of step a is accomplished through transfer hydrogenation orthrough pressure hydrogenation.
 3. The process of claim 2 wherein thehydrogen donor is in the form of hydrogen gas.
 4. The process of claim 1wherein the reducing of step a is accomplished through transferhydrogenation.
 5. The process of claim 1 wherein the optically activecatalyst comprises a transition metal complexed to at least oneoptically active ligand.
 6. The process of claim 2 wherein thetransition metal is one of a group consisting of: Ru, Rh, and Ir.
 7. Theprocess of claim 6 wherein the transition metal is Ru.
 8. The process ofclaim 7 wherein the optically active catalyst is one of the groupconsisting of: [(R)-HexaPHEMP RuCl₂ (R,R)-DACH], [(R)-HexaPHEMP RuCl₂(R,R)-DPEN], [(R)-PhanePhos RuCl₂ (S,S)-DACH], [(S)-PhanePhos RuCl₂(R,R)-DPEN], [(S)-MeO-Xylyl-PhanePhos RuCl₂ (R,R)-DPEN],[(R)-MeO-Xylyl-PhanePhos RuCl₂ (S,S)-DACH], [(S)-SynPhos RuCl₂(S,S)-DPEN], [(S)-Xylyl-BINAP RuCl₂ (S,S)-DPEN], [(S)-F-Phenyl-PhanePhosRuCl₂ (R,R)-DPEN], [(S)-MeO-Phenyl-PhanePhos RuCl₂ (R,R)-DPEN],[(S)-MeO-Phenyl-PhanePhos RuCl₂ (R,R)-DACH], [(R,R)-Me-DuPhos RuCl₂(R,R)-DPEN], [(R)-BINAP RuCl₂ (R)-DAIPEN], [(R,R)-Et-DuPhos RuCl₂(R,R)-DACH], [R,R-TsDPEN (Ru) (p-cymene) Cl], and [S,S-TsDPEN (Ru)(p-cymene) Cl].
 9. The process of claim 8 wherein the optically activecatalyst is S,S-TsDPEN (Ru) (p-cymene) Cl.
 10. The process of claim 4wherein step a is performed in the presence of an organic aproticsolvent.
 11. The process of claim 10 wherein the organic aprotic solventis dichloromethane.
 12. The process of claim 4 wherein the hydrogendonor is one of the group consisting of formic acid, ammonium formate,and 1,3-cyclohexadiene.
 13. The process of claim 12 wherein the hydrogendonor is formic acid.
 14. The process of claim 4 wherein the reductionof step a is accomplished in the presence of an azeotrope comprising anorganic base and a hydrogen donor.
 15. The process of claim 14 whereinthe organic base is triethylamine.
 16. The process of claim 1 whereinthe leaving group is a member of the group consisting of: sulfonateesters, and halides.
 17. The process of claim 16 wherein the leavinggroup is methane sulfonate ester.
 18. The process of claim 1 wherein R₁is H.
 19. The process of claim 1 wherein R₁ is

wherein R₂ and R₃ are as defined above.
 20. The process of claim 19wherein R₂ is methyl and R₃ is ethyl.
 21. The process of claim 20wherein the indanone derivative of step a is a compound of a formula:


22. A process for manufacturing a compound of the formula:

wherein R₁ is H, —OR₂, or

wherein R₂ is C₁-C₄ alkyl, and R₃ is H or C₁-C₄ alkyl, the processcomprising: a. reducing an indanone derivative of the formula:

wherein R₁ is defined as above, in the presence of an optically activecatalyst and a hydrogen donor to form a compound of the formula

b. activating the carbon in the —OH substituted benzylic position of theproduct of step a by converting the —OH to a leaving group; and c.reacting the product of step b with

to form the above desired product.
 23. A process according to claim 22further comprising transforming the product of step c into apharmaceutically acceptable salt.
 24. The process of claim 23 whereinthe pharmaceutically acceptable salt is the mesylate or tartrate salt.